Features
Acid test
How does the plethora of hyaluronic acid fillers compare in terms of performance, technology and safety profile? A panel from mixed disciplines discusses the merits of the products they use or helped develop
BELOTERO
Dr Laurence Hermitte is a biochemist engineer and managing director of Keysan Consulting. At Anteis, she helped develop CPM technology for its Belotero hyaluronic acids
Belotero fillers are dynamically cross-linked to obtain a cohesive matrix with different density zones. The process involves organising pure hyaluronic acid (HA) chains and initiating cross linking with butanediol diglycidyl ether (BDDE). Before the cross-linking has finished, the gel is swollen and more pure HA chains are added to the matrix. These added chains are cross-linked to the initial matrix but with fewer bonds, creating a compact gel with different density zones.
These density zones have paths that cross slightly and allow cells to accept Belotero as a native body. The filler uses cohesive polydensified matrix (CPM) technology creating a specific rheology—a long viscoelastic domain that this gel has a high mechanical resistance to.
A pilot study injected 11 fillers into the abdominal fat of four volunteers, 30 days prior to surgery. One was collagen-based, while the 10 others were cross-linked HA with BDDE using varying processes. All these fillers have the same nature, but are different in terms of structure and rheology.
The investigative team were able to identify, quantify and localise the immune cells. They also observed the fillers in the dermis and subcutaneous structures. They found that the early detection of cellular immune reaction seems to be a relevant criterion to compare the fillers. They observed no difference between day 14 and day 30. Apart from the two Belotero fillers, there was a pathological conspicuous immune reaction with all fillers at the injection site. They also observed the distribution of the implant and it was often irregular, with nodules present in some cases.
In all four patients, Belotero Basic showed histomorphological findings free of inflammation and homogenous distribution of the filler. So this study highlights the optimal tissue integration of these two fillers, whatever the depth of injection in the dermis.
Belotero does not contain any hard particles, allowing it to move according to muscle movements. Its cohesiveness in the density zones allows for lower local mechanical stress around the injection site. The filler is very malleable so there is no immune reaction and it is well accepted by the body.
Another prospective randomised blind randomised individual four-week study compared the effectiveness and tolerability of Belotero Basic versus Restylane. Twenty patients were injected on one nasolabial fold with Restylane, and on the other with Belotero Basic. Patients received one injection of each with a mean volume of 1.4ml. At screening, the severity of the nasolabial fold was rated between moderate and severe.
The primary endpoint was a quantitative comparison of the difference in treatment effect in mid-depth and evenness of the nasolabial target area from baseline to week four. They used a 3D Primos system, allowing for a 3D reconstruction of the skin’s surface.
After treatment with Belotero Basic, there was an approximate 110μm mean reduction of the fold. Restylane achieved a mean reduction of 72μm.
There was a slight tendency for Belotero Basic to be perceived as less painful and patients felt the presence of Belotero Basic less than Restylane. Around 55% of the subjects would recommend both fillers, 25% would recommend only Belotero Basic and 10% would recommend only Restylane. In terms of safety, there were no serious events reported, only erythema and haematoma which were mild to moderate in severity.
By using CPM technology, you can obtain highly cross-linked gels which still retain cohesiveness and cause less mechanical stress.
JUVEDERM
Mr Kambiz Golchin is a consultant ENT and facial plastic surgeon. He is a private consultant at UPMC Beacon Hospital and Blackrock Clinic in Dublin and medical director of the About Face Clinic in Dublin
As cosmetic practitioners, how do we decide which fillers we’re going to use in our clinics? We can use the five p’s of preference: product range, performance, profile in terms of safety and comfort, price, and prestige.
In terms of product range, Juvéderm has Juvéderm Ultra, a gentle, smooth, long-lasting gel; Voluma for volumising and recontouring the face; and Hydrate for hydrating the dermis.
The Juvéderm family caters for every indication on the face, so from the glabella to sleep lines to nasolabial folds and lips, and moving onto Voluma for cheek, mid-face and chin augmentation. It caters for all.
It uses cross-linked HA with BDDE as its cross-linking agent. It uses the 3D HA matrix; its concentration is 24mg per gram and it has FDA approval that the filler lasts for up to one year.
The 3D HA matrix gives more resistance to degradation, but also a much more uniform degradation of the product—patients won’t come back in six months with lumps, which particulate fillers can create. The filler is a smooth, cohesive gel which distributes evenly in the dermis so that you can give precise injections and precise filling.
This cohesive 3D matrix is the key. Test this by opening a syringe, putting a small amount between your thumb and index finger and try to stretch it. Juvéderm will stretch, meaning there is less product migration when you inject and it gives you natural, smooth results. Its easy-flow system—syringe design, luer lock and ultra-thin wall needles—makes it easy to inject. So in terms of performance, it ticks all the boxes.
In terms of rheology, Juvéderm Ultra Smile is clever. Rheology is the study and science of flow of unusual liquids. Water and oil would be usual liquids, but those with complex molecular structures, such as mayonnaise, peanut butter or HA gels, would be unusual liquids. Juvéderm Ultra Smile changes its viscosity and elasticity depending on the frequency of the movement, which makes it an ideal filler for lips. In terms of longevity, it is the only FDA-approved HA filler that lasts for 12 months.
The filler has a built-in anaesthetic—lidocaine—so it is a much more pleasant experience for the patient. The addition of lidocaine doesn’t change the rheology and doesn’t change the extrusion force, so it’s quite a natural synergy.
The product is safe. The rate of hypersensitivity and nodules are 0.002% and 0.003%. There are no reported cases of confirmed granulomas ever.
The last parameter is prestige—status, reputation, success and the level of respect at which one is regarded by others. Look around at key opinion leaders, successful aesthetic practitioners, their clinics, see what products they’re using and see what they’re saying in the media.
RESTYLANE
Dr Stefanie Williams is a consultant dermatologist. She is founder and medical director of European Dermatology London, based in Harley Street and Chelsea Bridge
The Restylane range has extensive amounts of clinical research. When you choose a filler, you have to consider safety above everything else.
One of the important points for a good safety profile of a filler is the high similarity to natural HA. We all have HA in our skin, and the closer we stay to the chemical structure of natural HA, the less of a problem with biocompatibility we will have.
You can measure this degree of modification with a spectroscopy and there is a formula—you can objectively determine a concrete
number, a degree of modification. If you used a non-modified HA (i.e. zero degree of modification), it wouldn’t give any lift, and would last only a few days so it wouldn’t be practical to use. You have to modify natural HA to make it workable as a filler.
Q-Med performed a study looking at a variety of fillers and examining the degree of chemical modification by cross linking. The average filler has 5–10% of chemical cross linking in its polysaccharide molecule. In comparison, the Q-Med NASHA products have around only 1% of chemical modification in their products. With a reduced degree of cross linking, you need less BDDE.
So why are we still left with such a strong gel that resists deformation? There are two ways of modification in the NASHA molecule. One is the traditional chemical cross linking, but the other is a mechanical entanglement.
Gel strength is another important parameter of an HA gel. When you have a strong gel, this gives you high longevity and high resistance to deformation, meaning it will have a good lifting effect that lasts a long time.
You can measure the gel strength objectively with in vivo rheology measurements. A weak gel will deform quickly under a wrinkle and will not maintain any volume correction. A strong gel will resist deformation. It will stay where you inject it because it doesn’t flow into the area of least resistance. Also, the higher the gel strength, the better its lifting capacity.
Another study by Q-Med showed the gel strengths of a variety of common HA fillers on the market. NASHA fillers were shown to have the best lifting capacity, despite having the lowest degree of chemical modification. This high gel strength is thought to be caused by the additional mechanical entanglements, in addition to its chemical cross links.
If an HA gel were a single piece of gel, it can be stretched and bent, but cannot flow and therefore cannot be injected with a syringe. The gel has to be cut into little particles to give the product the ability to flow and enable it to be injected. All HA fillers contain particles, as a fact. They have to, otherwise they cannot be injected. These HA particles then attract water, swell up and sit densely together in a monophasic solution.
NASHA products have a proven clinical evidence and safety record from many clinical studies and more than 11 million treatments. Its high lifting capacity is good for volumising and deep folds and it has a good long-term residence time.
But one of the most important points is that any HA product can only be as good as its injector. While it is important to look for the different features that a filler can offer, practitioners should also consider support and ongoing training provided by the filler company, with advanced training courses and ongoing support.
REVANESSE
Dr Martyn King is a cosmetic physician and owner of Cosmedic Skin Clinic in Birmingham
As a cosmetic doctor I need to ask, “What do I need from a filler?” Different technologies separate the fillers but ultimately, when I have a syringe in my hand, I want to know that it is safe.
I also want to know that the product does what it says on the tin, and that it can volumise and correct. Patient satisfaction is important, as well as a wide range of indications, a good product range and evidence-based clinical studies.
It needs to be easy to inject with low-extrusion force and stays where it is injected. We don’t want migration of product and it needs a long shelf life—you don’t want to buy a product that you have to use within a few weeks.
In terms of contraindications, we don’t want to be doing patch testing. There should be low incidents of adverse events, good company support and training, and it should be cost effective.
Revanesse seems to tick all these boxes. Its technology has been developed by Prollenium, which has a strong focus on the aesthetic market in terms of dermal fillers, implants, skin care products, facial surgery products and injectables.
The Revanesse family is biodegradable, non-animal based and comes in the form of a clear HA gel which is safe to use, non-toxic, easy to inject, does not migrate from the injection site and will last for a long time.
But not too long—this is also important. If you’re using products that last years and years then you’ve lost that client for a long time. You want a product where people want to come back.
The portfolio range can be used for different depths and indications. While it doesn’t yet have FDA approval—this is expected by early 2012—it is approved across Europe in 52 countries.
You can use Revanesse all over the facial area. Each product is targeted for different areas and effects, for fine lines, medium lines or volumisation.
Revanesse filler concentration is 25mg per ml. Revanesse Pure is used for rehydrating the skin and replacing lost HA. It has a slightly lower concentration at 14mg per ml of HA. Revanesse is for mild to moderate lines and has a concentration of 25mg per ml. Revanesse Ultra is a more viscous product and more suitable for re-sculpting and volumisation. Revanesse Lips is for lip augmentation and definition. The products report a 60% satisfaction rate for both patient and physician.
Many filler manufacturers talk about the technology and how they perform the cross linking, and Revanesse is no different. It uses thixotropic cross-linking technology.
The osmolarity pH is balanced. When you’re injecting the skin, it’s not drawing water. You do not need to overcorrect—in the past, we’ve been advised to over-inject because of the initial loss when the oedema settle down.
While the filler slowly degrades over time, it doesn’t result in complete loss of volume. It does tend to maintain its integrity while it degrades.
It has a very low rate of adverse events, and is endotoxin free. In terms of protein concentrations, Revanesse has two parts per ml, which is very low.
A blinded study using Restylane for nasolabial folds showed better initial volume correction with Revanesse Ultra and better results according to patients and physicians on follow-up. Another 130-patient study at four sites compared Revanesse Ultra and Restylane in the nasolabial fold, with a six-month follow up. Again, this showed it was safe and effective with equal or better results.
Outcome data comparing Revanesse Ultra to Restylane in terms of the wrinkle severity rated scale and global aesthetic improvement scale showed no real difference between the two.
EMERVEL
Dr Chantal Belin is a quality and regulatory support manager for Symatese Research & Development
To create the Emervel range of HA fillers, we developed new physical, chemical and pre-clinical evaluation methods to investigate the fillers available in the market, from best to worst, to understand how they work and to connect the physical and chemical properties
with efficacy and tolerance.
The knowledge we gained allowed us to develop products and customise them to the needs of the patient and physician.
To produce the ideal filler, we connected the dots between physical and chemical product key-quality attributes and the resulting product host-interaction of tolerance and performance. Emervel is a result of optimal balance technology, based on the three Cs: cross linking; calibration; and concentration. This technology allows for optimal gel texture for each indication with optimal tolerance and longevity.
Cross linking is the connection between two HA chains with BDDE. If you don’t cross link you don’t have firmness. We measure the cross linking through rheology and the G-prime. The higher the cross line, the higher the G-prime, the firmer the filler and the more resistance to deformation. So while you need high cross linking for an efficient filler, that’s not all. We’ve seen that the higher the cross
linking, the higher the inflammatory reaction.
For a G-prime of around 100, as with Emervel, the result is quite clean. For a G-prime around 350, you start to see macrophages around the external surface of the filler. With a G-prime measurement of 1000, there are lots of macrophages around the filler and this is directly connected to hardness of the implant, erythema and longevity.
So cross linking brings firmness to the HA, but it impacts tolerance and patient comfort. With the Emervel range, we have four different cross-linking degrees adapted to match the indication.
Calibration is a sieving process. The gel goes through a calibrated grid which gives a homogeneity to the gel—when the gel is produced, cross linking creates blocks. For optimum injectability we need calibration to adapt the gel according to tissue specificity. For a comfortable injection, different factors affecting the injection force such as the syringe and the needle, and the calibration size. Moreover the higher the gel concentration, the higher the injection force and the presence of uncross-linked HA that reduce the injection force.
Calibration size also plays a role on flow regularity because if it’s much larger than the inner diameter of the needles, the gel breaks entering the needles and you will feel it when you’re injecting. The physician is then doing the calibration if the size of the needle and the particles do not match properly.
With Emervel, we have chosen an optimal syringe diameter with ultra-thin wall needles. Our gel calibration is in line with the needle’s inner diameter so we have a smooth and comfortable injection without the need of free soluble HA.
The calibration is also useful to adapt the gel according to tissue specificity. The bigger the calibration, the easier to keep its shape and the better its lifting capacity. For superficial injection you would need a more dispersible product with low-lifting capacity, so a small calibration. But for deeper injection you need high-lifting capacity and less dispersible product, so a larger size of calibration.
The Emervel range benefits from three different lifting capacities.
Concentration impacts injectability, longevity and tolerance because products below 10mg per ml do not last long. Too high an HA concentration gives a higher G-prime, increases the risk of inflammation and is more difficult to inject. We have chosen one HA concentration that does not stimulate the macrophagic degradation process.
UMA JEUNESSE
Mr Peter Sharma is a consultant NHS surgeon and medical director of Cambridge Medical Aesthetics
HA plays a critical role in differentiation, motility, morphogenesis and wound healing. But if you injected pure HA, it wouldn’t last very long—the half-life of pure HA is about 24 hours so you have to cross-link it to make it reside in the tissue for longer.
The most important building blocks of HA-based dermal implants are HA as the base material and additives like buffers, water and the cross-linking agent.
The basic cross-linking technology is still used by more than 99% of manufacturers. You add the cross-linking agent to HA and it turns into a thick, gum-like material that you can’t inject. It is fragmented and the fragmented particles are suspended in pure HA aqueous solution and the final product is a suspension.
When you subject a suspension to shear stress inside a 27G or 30G needle, the particles segregate. They stay in suspension because the gel has high viscosity. As soon as you subject them to shear stress, they cause obstruction, so you have to apply more pressure while injecting.
This plug causes pressure inside the needle to build up to such a degree that the plug is expelled with an explosive force. The result is blobs of implant deposited in the skin which causes gaps, and you then have to massage.
Most contemporary HA-based fillers are derived from molecularly dispersed soluble monomers, multifunctional cross-linkers and macromers. Traditional fillers are randomly interconnected, lack structural complexity, mechanical integrity, functional diversity, which you see in the extracellular matrix (ECM). The ideal goal should be to mimic the ECM.
Uma Jeunesse is based on a new technology of micro into sub-micro dimensions and synthesising the HA-based doubly cross-linked networks, the viscous elasticity, the particle size, surface functional group and intra-particle cross linking.
The end result is a significant reduction of cross-linking agent. The molecule is designed to replicate the enzymatic molecular
mechanism of HA degradation and viscosity—a process where the molecule is imparted, a 3D spring-like property to the homogenous molecule. There is also a significant reduction of the endotoxin levels.
The closer the gel hardness is to ECM, the more biocompatible the filler will be. The gel hardness of ECM is difficult to measure but it’s around 160 particles. The gel hardness of Uma Jeunesse is about 150–170 particles, compared with 200–600 particles for most fillers.
Viscosity of a product is determined by its composition and degree of cross-linking. The viscosity of Uma Jeunesse is about 30,000 milli-particles, which is very close to the ECM. Other fillers vary between 50,000–55,000.
Most modern dermal fillers are based on HA of synthetic origin. The endotoxin level in most fillers documented in the literature is about 0.5EU/ml. Uma Jeunesse is less than 0.1EU/ml. Over the past year, there have been no adverse events reported in the UK.
The choice of the cross-linking agent is important because most cross-linking agents are toxic. While BDDE is slightly less toxic, if there are large residual quantities of it in the product, injection site reactions will be seen.
Uma Jeunesse uses BDDE, but virtually all of the cross-linking agent has been removed. The residual BDDE in Uma Jeunesse is less than 1PPM. Most products contain 5PPM.
Molecular weight of synthetic HA varies between 2–2.5 million daltons and the synthetic high-molecular weight is used in Uma Jeunesse.
The concentration of HA is 24mg/ml. Most products have 70–80% cross-linked HA. Uma Jeunesse has more than 96% cross-linked HA.
Cross-linked HA will shrink and you will see a loss of aesthetic effect. If 96% is available for correction of the wrinkle, the aesthetic effect will not be lost.
Shelf life of Uma Jeunesse is three years; other fillers have two years. Injection site reactions, such as itching, bruising and discolouration, are virtually unknown. Pain is less than 18%, while other fillers see 60–90% pain reactions.
Uma Jeunesse has less than 16% lumpiness, while other fillers have around 80% incidence.
STYLAGE
Dr Alain Lajeunie is a mesotherapist and aesthetic practitioner, and has provided training in both since 1999
The Stylage range comes from Vivacy, a French manufacturer which specialises in design manufacturing and distribution of HA. The first innovation involved Restylane’s non-animal stabilised HA. The second generation had monophasic gel with Juvéderm, Teosyal and Esthelis. The third generation is now with Stylage—a non-animal HA with monophasic gel, multi cross-linked with an antioxidant.
Stylage uses interpenetrated cross-linked network (IPN-like) technology, which requires less BDDE. This results in a safe, long-lasting product for all skin types. It contains mannitol, a natural antioxidant that acts against free radicals. It has optimised elasticity for easy modelling and reshaping, even for delicate areas like the nose, temples and hands. It has a high viscoelasticity for good filling capacity and natural aesthetic results thanks to its smoothing effect.
With IPN-like technology, you have two structures—the monophasic A and B structure, and the IPN-like structure. The two are mechanically independent, so Stylage is easy to inject and the increased density of its cross-linking nodes make it long-lasting. Products in the range include Stylage HydroMAX for mesotherapy, Stylage S for fine lines, Stylage M for medium wrinkles, Stylage L for deep wrinkles, Stylage XL for depressions and Stylage Lips.
You can combine products for targeted treatment, such as injecting classic products deep into the skin and the mesotherapy gel
superficially in a single procedure.
Stylage Lips and Stylage M are also available with Lidocaine to reduce pain for the patient. The filler concentrations are: S, 16mg; M, 20mg; L, 24mg; and XL, 26mg. Stylage Lips is between S and M with 18.5mg concentration.
Free radicals are one of the major causes of cell destruction and damage to elastin and collagen fibres, micro-polysaccharides and the lip membrane. Skin becomes thinner, atrophic, ruptured and wrinkles appear. During the injection you also have an inflammatory reaction with the production of superoxide radical and hydroxyl radical, which attack the HA and adjacent cells.
The antioxidant mannitol is naturally present in nature in celery, olives and raspberries, and is well tolerated in the skin. Mannitol scavenges free radicals and provides optimal resistance to degradation. The average satisfaction index showed a clinical evaluation of 96%, followed by eight investigators during one year. The products have good durability and tolerance and are used in more than 20 countries.
Stylage HydroMAX is a mesotherapy product, so treats the signs of ageing, not wrinkles. It complements the effects of Stylage. There are two injection techniques, superficial micro injections and the PPP technique, for restructuring the tissue and smoothing the wrinkles.
